The human hemoglobinopathies are genetic disorders of widespread occurrence with varied clinical and laboratory manifestations. An understanding of the molecular events leading to these phemotypes is of importance not only in furthering our basic understanding of gene structure and function, but also in helping to plan strategies for alleviating these disorders. The genes for normal alpha- and beta- like globin chains have already been examined in detail using Charon bacteriophage cloning vectors. I now propose to employ a cosmid vector system to clone and examine larger contiguous DNA regions in the globin-gene complex from patients with altered globin-chain production. The objectives are threefold: 1) Isolate these large gene regions by molecular cloning into cosmid vectors. 2) Characterize and map the genes and flanking DNA regions by restriction endonuclease and DNA heteroduplex analyses, and compare nucleotide sequences from selected regions with sequences from normal individuals. 3) Use the cloned genes in functional studies to relate nucleotide sequence modifications with gene structure and function.